Researchers at the Department of Medicine have developed a novel therapeutic which could reduce the risk of disease caused by a particular virus infection (human cytomegalovirus, HCMV) after stem cell transplants. They have repurposed an established anti-cancer therapy to create a fusion-toxin that specifically targets and kills infected cells from transplanted tissue. The work has recently been published in Nature Communications February 2017.
HCMV is a common virus, infecting 65% of the world’s population, which is a major threat to those with compromised immune systems. In particular, HCMV poses a serious risk to stem cell transplant recipients, whose immune systems take time to recover after transplantion. Currently, these patients are treated immediately with drugs against HCMV before they show symptoms, known as prophylaxis. Prophylaxis however disrupts the patient’s immune functions and is not always effective: 10% of patients still develop CMV disease with treatment. CMV disease is characterised by infection of multiple organs with HCMV, and has a high mortality rate.
HCMV is such a threat in this setting because the virus resides in the stem cells themselves, and so can be carried from donor to recipient. The virus cannot be easily removed from the transplant because it establishes a latent infection. Latency is very close to being dormant; the virus stops replicating and expresses very few genes, allowing it to avoid the immune system. After transplant, the virus reactivates and can spread, unimpeded, through the immune-compromised patient, causing CMV disease. Conventional drug treatments against HCMV can only target the replicating virus, and so are ineffective against latency.
“Tissue from donors carrying the virus often has to be used for transplants because there are so few donors and so many people carrying the virus,” said Professor John Sinclair. “By transplanting bone marrow, you’re giving the patient the virus and you’re immune-suppressing them. That’s the worst of both worlds. Any treatment which could kill latently infected stem cells would be clinically very beneficial.”
Researchers at the Department of Medicine identified a new gene that HCMV expresses during latency, called US28. The protein coded by the US28 gene is found on the surface of the cell, and attaches to a protein called fractalkine, pulling fractalkine proteins into the cell. This positioning of US28 protein made an ideal drug target. A collaboration was established with HCMV researchers at the Technical University of Denmark (DTU), who developed a fusion toxin protein that sticks to US28. Fusion toxin proteins consist of a protein “hook”, which sticks to a target cell with high affinity, attached to a toxin, which is dragged into the cell after attachment and kills the infected cell. The method allows researchers to target cells in a highly specific manner and is already successful against some cancers. Researchers at DTU developed a fusion toxin protein against the US28 protein, by making a mutant version of the molecule fractalkine. This is the first time that a fusion toxin protein has successfully been directed against a virus.
In Cambridge, researchers showed that the fusion toxin protein, named F49A-FTP, is able to target latently infected cells in a specific manner, and kill them, thereby greatly reducing the rate at which HCMV can reactivate in cell culture. It is hoped that this proof of principle could be moved into clinical trials, to protect vulnerable patients from CMV disease and that this approach could be directed against other, similar, viral infections.